The complement (C) system is one of the most important humoral defense systems in man. Activation of either the classical C pathway (C1 through C9) or the alternative C pathway (B, D and C3 through C9) results in the production of biologically active macromolecules and fragments of C components which may be either protective or damaging to the host. Previous investigations of the role of C in disease have primarily focused on changes in serum concentrations and the tissue deposition of C components. We propose for the first time to evaluate the importance of genetically determined polymorphic variants of C components and the relationship to the development of renal disease in children. Despite the remarkable polymorphism of nine of the eleven C components the significance of this polymorphism is not known. Our specific aims are: (1) to determine the frequency of the C4, C3 and B phenotypes in a variety of childhood renal diseases as compared to controls; (2) to correlate C phenotypes with the response to pneumococcal vaccine; (3) to compare biological activities of different C variants (i.e. hemolytic activity, solubilization of immune precipitates) and (4) to correlate C phenotypes with HLA-DR antigens and T-cell subsets. C typing is performed by prolonged electrophoresis in agarose by methods established for C3 and B, and for C4 by recently described methods using neuraminidase treated plasma. Functional C assays employ published methods. Our preliminary evidence shows significant variation from normal for the frequency of certain C phenotypes in the idiopathic nephrotic syndrome, IgA nephropathy, anaphylactoid purpura, recurrent hematuria and juvenile onset lupus erythematosus. Our long term goal is to perform extensive typing of childhood renal disease and to determine whether functional variations can be detected between C phenotypes which may explain a relationship to the development of these diseases. Confirmation of our preliminary findings and the detection of functional differences would present new and potentially important areas of research into the etiology of these common pediatric nephropathies.